Barrett's esophagus is the precursor of most esophageal adenocarcinomas and a large proportion of esophagogastric junctional adenocarcinomas. These diseases are closely associated with gastroesophageal reflux. Endoscopy is therefore recommended for the evaluation of chronic gastroesophgeal reflux symptoms. Endoscopic surveillance, performed in those identified with Barrett's esophagus, detects cancer at an early stage. However, the large majority of these cancers occur in those with previously undiagnosed Barrett's esophagus and nearly half of these persons have no history of gastroesophageal reflux symptoms. Identification of genetic risk factors would lead to an improved understanding of the molecular pathogenesis of these diseases and more directed screening of family members. Our research has characterized familial aggregation of Barrett's esophagus and its associated cancers, which we term Familial Barrett's Esophagus (FBE). We have developed a network of investigators at eight centers who are actively identifying and accruing FBE families and biobanking lymphoblastoid cell lines in a centralized biorepository. Our segregation analysis of accrued pedigrees suggests that FBE is the manifestation of autosomal dominant susceptibility alleles. Our central hypothesis: